Vitamin D.sub.3 (cholecalciferol) has been known for many years. It may be prepared from cholesterol by the introduction of an additional bond into the cholesterol molecule to produce 7-dehydrocholesterol and subjecting the 7-dehydrocholesterol to ultraviolet radiation. It was at one time thought to be biologically active in the regulation of intestinal calcium transport and the mobilization of calcium from bone. More recently it has been discovered that to be biologically active cholecalciferol has to be hydroxylated in the body to 25-hydroxycholecalciferol or hydroxylated derivatives thereof, particularly 1.alpha.,25-dihydroxycholecalciferol. It would, therefore, be important to prepare and administer such hydroxylated derivatives, particularly 1.alpha.,25-dihydroxycholecalciferol, instead of Vitamin D.sub.3.
The synthesis of 25-hydroxycholesterol, a precursor of 25-hydroxycholecalciferol, by practical methods is set forth in my co-pending patent applications Ser. No. 816,478 filed July 18, 1977 now U.S. Pat. No. 4,183,852 and Ser. No. 829,009 filed Aug. 30, 1977 now U.S. Pat. No. 4,134,904. It would now be important indeed to discover practical and effective methods for the synthesis of 1.alpha.,25-dihydroxycalciferol and its derivative 1.alpha.,25-dihydroxycholecalciferol.
Earlier publications disclosed the synthesis of 1.alpha.,25-dihydroxycholesterol from cholesterol and stigmasterol. In these syntheses intermediates for the 1.alpha.-hydroxylation were needed which had a 6-ketone group in the steroid nucleus in addition to a 3-keto group, which could be obtained by the oxidation of the 3-hydroxyl function. Since cholesterol and stigmasterol have a 5,6-double bond, the required 6-keto group had to be introduced synthetically in several steps.
The first synthesis of 1.alpha.,25-dihydroxycholesterol started from an oxidation product of cholesterol (E. J. Semmler, M. F. Holic, H. K. Schnoes and H. S. DeLuca, Tetrahedron Letters, 4147 (1972)). In this synthesis, the 1.alpha.-hydroxyl group was introduced into the steroid nucleus through an intermediate containing a 6-keto group. Since cholesterol has a 5,6-double bond, the 6-keto group had to be introduced synthetically. This required three operations, nitration, reduction and acid hydrolysis, to produce the 6-keto intermediate. In another synthesis, which started with stigmasterol (T. A. Narwid, J. F. Blount, J. A. Iacobelli and M. R. Uskokovic, Helvetica Chim. Acta, 57, 781 (1974)), treatment of 25-hydroxycholesterol acetate with diborane followed by the addition of hydrogen peroxide, yielded a mixture of which the main component was a triol. This triol was then oxidized to the 25-hydroxy-3,6-dione, from which the 1.alpha.,25-dihydroxycholesterol was synthesized.
In the procedures above described the introduction of the 6-keto group occurred in advanced stages of the synthesis, where even small losses of material add significantly to the cost of producing the final product.